CHAPTER 3: Basic Biological Mechanisms of Photodynamic Diagnosis/Photodynamic Therapy

Biological processes in photodynamic diagnosis and tumor therapy start with the delivery of a suitable photosensitizer (PS), transportation via the vasculature and selective accumulation in the tumor, including tumor cells, tumor vessels, extracellular matrix, stroma cells and immune cells. Subsequently, the PS penetrates the cell membrane and localizes intracellularly in different compartments. With time, relocalization within the cell may occur. The site of localization is decisive for the intracellular site of damage. Even without irradiation and activation, the PS may exert some cytotoxic or at least cytostatic effect. By irradiation of the PS with a suitable wavelength in the visible range, the PS is detectable by fluorescence and reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated, which oxidize mainly proteins, lipids and DNA. The amount of primary damage to the cells depends on many parameters, including immediate and late antioxidant strategies. At low doses, the cells are able to quench ROS/RNS and adapt to the conditions. With increasing but still sublethal doses, which are relevant in diagnosis as well as in therapy at deeper tissue layers, damage repair and—in some cases—a stimulatory effect on cell growth is observed. In addition, the cell may start autophagic processes in order to prevent cell death. Immune reactions are induced, which may attack the tumor and even generate systemic anti-tumor immunity. At lethal doses, cells die by apoptosis, necrosis or rare cell death modalities such as autophagic cell death. Photodynamic therapy-induced apoptosis is carried out via the mitochondrial or the receptor-mediated pathway, starting with ROS either directly or indirectly via the endoplasmic reticulum stress pathway or via damaged lysosomes. Cells die necrotically if the damage is so massive that it decreases the cellular energy level or disrupts the cytoplasmic membrane. In addition, indirect cell killing by cytotoxic immune reactions or by hypoxia following vasculature targeting may occur. Furthermore, damage to the tumor microenvironment contributes to tumor elimination.